Friday, July 28, 2006

Those two pitches account for approximately 95% of all spam, right? But what if you could manufacture one drug that promises to do both things? Think of the profits!!

Although it sounds too good to be true, there may yet be such a substance: drugs acting as agonists at the melanocortin 4 receptor (MC4-R). A recent article in Neuron focused on the weight loss aspects of MC4-R. Serotonergic agents were administered to obese and regular mice; both groups reduced their food intake as a result. The figure above illustrates how serotonin is thought to act on melanocortin pathways (via actions at the serotonin 1B receptor, 5-HT1BR).

Translated, the arcuate nucleus of the hypothalamus may play a central role in appetite suppression. The arcuate has two populatons of neurons: one expressing the anorectic melanocortin receptor agonist, a-MSH (green neuron) and the other expressing the appetitite-stimulating melanocortin receptor antagonist, AgRP (blue neuron). The combined increase in a-MSH and decrease in AgRP act at downstream MC4 receptors to suppress appetitite.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT(1B)Rs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

However, the serotonergic drugs given to the mice in that study included D-fenfluramine, part of the scary and dangerous fen-phen fiasco. Fen-phen was linked to heart valve disease and pulmonary hypertension, and was withdrawn from the U.S. market in 1997. The mice were also given an experimental 5-HT1BR agonist not yet approved for human use.

Are there any drugs that act directly at MC4-R? And what about sexual function? Where is that miracle aphrodisiac weight loss supplement you promised??

If MC4R agonists induce spontaneous penile erections in men, this would represent a significant impediment to the development of compounds to treat obesity.

The nonselective melanocortin agonists, 1 and 3, have nausea and vomiting as adverse side effects when administered to humans either subcutaneously or intranasally. Attempts to study whether the effects of these two structurally related molecules are mechanism-based have been of limited utility.

Wednesday, July 26, 2006

In a neuroanatomical tour de force, Nimchinsky and colleagues (1999) obtained access to samples of the anterior cingulate cortex (and other cortical regions) from 28 different primate species, from prosimians to anthropoids to great apes to humans. They processed the samples with a Nissl stain to identify neuronal cell bodies in the cerebral cortex, a structure that (generally) consists of six layers. Spindle neurons are a unique type of neuron found in layer Vb in the ACC and frontoinsular cortex of humans. This is nothing new; spindle neurons (also called Von Economo neurons) were first identified in the 19th century by W. Betz (of the eponymous Betz cell fame, I presume) and by Nobel laureate Santiago Ramón y Cajal. What was new in 1999 was the finding that only humans and great apes have spindle neurons.Nimchinsky EA, Gilissen E, Allman JM, Perl DP, Erwin JM, Hof PR. (1999). A neuronal morphologic type unique to humans and great apes. Proc Natl Acad Sci 96:5268-73.

We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal possible adaptive changes and functional modifications over the last 15-20 million years in the anterior cingulate cortex, a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes. That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer's disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution.

Our lab has investigated the anatomical structure of the Von Economo (spindle) neurons in anterior cingulate and fronto-insular cortex. Based on functional imaging studies of these brain areas and our studies of the expression of neurotransmitter receptors on these cells, we think they participate in fast, intuitive social decision-making. We have found that the Von Economo neurons emerge mainly in the first three years after birth. We also have evidence that in autistic subjects the Von Economo neurons are abnormally located, possibly as a result of a migration defect. This abnormality may be at least partially responsible for defective social intuition in autism.

Somehow, the "spindle neuron" meme hasn't caught on like the "mirror neuron" meme. Is it because spindle neurons have been only been described anatomically (not physiologically), while the reverse is true for mirror neurons? Anatomically speaking, do we know much about mirror neurons? Here's what Rizzolatti and Craighero (2004) have to say about them:

Mirror neurons are a particular class of visuomotor neurons, originally discovered in area F5 of the monkey premotor cortex, that discharge both when the monkey does a particular action and when it observes another individual (monkey or human) doing a similar action (Di Pellegrino et al. 1992, Gallese et al. 1996, Rizzolatti et al. 1996a).

In the elegantly titled article, The importance of being agranular, Stewart Shipp reviews evidence that approximately 10% of recorded cells in premotor area F5 in the macaque monkey can be classified as mirror neurons. He also points out an interesting conundrum regarding the anatomical organization of motor cortex: it's agranular, meaning it's lacking the granule cell layer (layer IV), the typical termination point for feedforward sensory information. Area 7b (or PF) in the rostral inferior parietal lobule provides the main parietal input to F5. Without going into too many details, it seems the anatomical circuitry of visual input to F5 is pretty complicated. Anyone who studies mirror neurons (or who does fMRI studies of "empathy and the mirror neuron system") should read these two papers:

Horror, like comedy, has always been something of a reptilian-brain endeavor, unusual among the arts insofar as it is successful only when it is able to produce a single, audible emotional effect — a scream or a laugh — that is primal, cathartic and difficult to understand. This is one reason that horror has always been a director's medium: the horror movie is a contraption, and it takes a certain organizational flair to design, pace and frame a scare.

The major goal of the present functional magnetic resonance imaging study was to investigate the influence of disgust sensitivity on hemodynamic responses during disgust induction. Fifteen subjects viewed three different film excerpts (duration: 135 s each) with disgust-evoking, threatening and neutral content. The films were presented in a block design with four repetitions of each condition. Afterwards, subjects gave affective ratings for the films and answered the questionnaire for the assessment of disgust sensitivity (QADS, []). The subjects' overall disgust sensitivity was positively related to their experienced disgust, as well as to their prefrontal cortex activation during the disgust condition. Further, there was a positive correlation between subjects' scores on the QADS subscale spoilage/decay and their amygdala activation (r=0.76). This was reasonable since the disgust film clip depicted a cockroach-invasion and the subscale spoilage/decay contains, among others, an item asking for disgust towards cockroaches. The study stresses, in accordance to previous studies, the importance of considering personality traits when studying affective responses in fMRI studies.

For those into such things, there's a good analysis of that horror flick By PAUL KESLER.

Fundamentally, Carnival Of Souls is a visual exploration of death, which, in the course of this exploration, sees death from a subjective point of view that is at times reminiscent of Carl Dreyer's "Vampyr". However, its subjectivity is far more radical than that of the Dreyer film, since Dreyer, concentrating to some extent on actual occurences rooted in a particular time and place, dwelt only sporadically on the inner consciousness of his protagonist. By contrast, it could be argued that everything in Carnival Of Souls other than the physical death of the main character is subjective in nature. As a result, we are forced into suspension of disbelief as to the reality-status of a woman who, though materially dead, continues to experience many things through "normal" consciousness.

In the study of Stark et al. (2005),

Three film clips (DISGUST, FEAR, NEUTRAL, 135 s each) with sound track were presented to the subjects. Each clip was a scene selected from a commercial movie: DISGUST showed an invasion of cockroaches, a scene from the movie Creepshow I (Romero and Rubinstein, 1982). FEAR was drawn from The Hitcher (Harmon et al., 1986) and depicted a boy threatened by a man armed with a knife. NEUTRAL came from Switzerland—The Alpine Wonderland (Scro et al., 1989) and showed urban areas.

The paper was mostly about disgust and how the participants' self-ratings on a disgust sensitivity questionnaire correlated with neural responsiveness in the orbitofrontal cortex, medial prefrontal cortex and the amygdala. Are the contestants on Fear [and Disgust] Factor screened with such questionnaires before going on the show??

Friday, July 21, 2006

It's been so long since The Neurocritic began a plodding series on hypnosis (June 6 to be exact), that the in press articles are now in print in the Journal of Physiology (Paris). The final topic for discussion is the use of hypnosis to control pain.

. . . Second, we looked at the anti-nociceptive effects of hypnosis. Compared to the resting state, hypnosis reduced pain perception by approximately 50%. The hypnosis-induced reduction of affective and sensory responses to noxious thermal stimulation were modulated by the activity in the midcingulate cortex (area 24a′). Finally, we assessed changes in cerebral functional connectivity related to hypnosis. Compared to normal alertness (i.e., rest and mental imagery), the hypnotic state, significantly enhanced the functional modulation between midcingulate cortex and a large neural network involved in sensory, affective, cognitive and behavioral aspects of nociception. These findings show that not only pharmacological but also psychological strategies for pain control can modulate the cerebral network involved in noxious perception.

What are some of the brain regions involved in the perception of pain? A meta-analysis of 35 imaging studies is illustrated below.

By way of explanation, back in January, I became addicted to BrainMap,

an online database of published functional neuroimaging experiments with coordinate-based (Talairach) activation locations. The goal of BrainMap is to provide a vehicle to share methods and results of brain functional imaging studies. It is a tool to rapidly retrieve and understand studies in specific research domains, such as language, memory, attention, reasoning, emotion, and perception, and to perform meta-analyses of like studies.

A neuroimaging study examined the neural correlates of social exclusion and tested the hypothesis that the brain bases of social pain are similar to those of physical pain. Participants were scanned while playing a virtual ball-tossing game in which they were ultimately excluded. Paralleling results from physical pain studies, the anterior cingulate cortex (ACC) was more active during exclusion than during inclusion and correlated positively with self-reported distress. Right ventral prefrontal cortex (RVPFC) was active during exclusion and correlated negatively with self-reported distress. ACC changes mediated the RVPFC-distress correlation, suggesting that RVPFC regulates the distress of social exclusion by disrupting ACC activity.

More on that topic later.

[But I think I might actually like this study -- relatively speaking -- since it doesn't equate social rejection with physical pain.

This study investigated human anterior cingulate cortex (ACC) involvement during a task that dissociated expectancy violation from social rejection. Across two studies, participants underwent functional magnetic resonance imaging while making social judgments and receiving fictitious feedback that was either positive or negative and consistent or inconsistent with their expectations. The results demonstrate that the dorsal ACC is sensitive to expectancy violations, whereas the ventral ACC is differentially responsive to social feedback.]

Now back to physical pain. OK, here's another ALE map that shows clusters of activation (below). In this map, different clusters of activation are coded with different colors. The first map (above) was color-coded for significance level.

Technical details: ALE is a quantitative meta-analysis method (Turkeltaub et al., 2002) that can be used to infer function-location relationships from the functional neuroimaging literature. At the time of this analysis, BrainMap, a Java software application developed at the Research Imaging Center in San Antonio, contained 35 papers reporting activations in studies that delivered painful stimuli to the participants, and 34 of these were included in the meta-analysis. The Talairach coordinates of all pain-related activations were used to estimate voxel-wise activation likelihoods. A false discovery rate threshold of p less than .05 and a cluster extent threshold of 100 mm3 were applied to the ALE map. The resulting map identified the regions of activation common to all studies comprising the meta-analysis. Sixteen clusters were identified, with the largest being centered in the thalamus, insula, and cerebellum.

So there's evidence (Kulkarni et al., 2005) for a lateral pain system (ventral lateral nucleus of the thalamus, primary and secondary somatosensory cortices), a medial pain system (medial thalamic nuclei, anterior cingulate cortex, other prefrontal regions, and the fearful amygdala), and the intermediate insula, which sits between them. The lateral system is related to the sensory aspects of pain, while the medial is related to more "perceptual/affective" components of pain. What hypnosis does is to increase activity in the ACC, which may then downregulate activity in the sensory regions (see also Faymonville et al., 2000). 1

ADDENDUM: Interestingly, the opposite manipulation has also been examined (Raij et al., 2004; Derbyshire et al., 2004). Hypnotically-induced pain activates the same pain matrix as real pain, but with less activity in the sensory areas.

Wednesday, July 05, 2006

You've probably heard about the case of Terry Wallis, a 42 year old man in Arkansas who spent 19 years in a "minimally conscious state" following severe traumatic brain injury. Then one day he saw his mother walk into the room and (after not speaking all those years) said "Mom."

The Aspen workgroup defined the minimally conscious state (MCS) as a condition of severely altered consciousness in which the person demonstrates minimal but definite behavioral evidence of self or environmental awareness (Giacino et al, 1997).

A number of bloggers have commented on how his case is different from that of Terry Schiavo, who was in a persistent vegetative state (not a MCS).

What I'll focus on here is the work of researchers at Cornell, who followed Mr. Wallis using diffusion tensor imaging (DTI) and PET scanning over an 18 month period.

Using a novel technique, they saw evidence of new growth in the midline cerebellum, an area involved in motor control, as Mr. Wallis gained strength and range in his limbs. Another area of new growth, located along the back of the brain, is believed by some experts to be a central switching center for conscious awareness.

We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patient’s DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.

In a commentary on the article, Laureys, Boly, and Maquet note the importance of the precuneus in conscious awareness:

The most remarkable finding in the Voss et al. study (12) was the MRI assessment of transiently increased fractional anisotropy and directionality in the posterior midline cortices (encompassing the cuneus and precuneus), interpreted as increased myelinated fiber densities and novel corticocortical sprouting, paralleling the emergence of the patient from MCS. The same area of the patient’s brain also showed amplified metabolic activity, as measured by PET. This finding stresses the importance of the posterior medial structures in consciousness of self and interaction with the environment (14, 15). Activity in the medial parietal cortex (i.e., precuneus) seems to show it to be the brain region that best differentiates MCS from VS patients (16). Interestingly, this area is among the most active brain regions in conscious waking (15) and is among the least active in altered states of consciousness, such as pharmacological coma (17), sleep (18), dementia (19), Wernicke-Korsakoff syndrome, and postanoxic amnesia (20). It has been suggested that this richly connected multimodal posteromedial associative area is part of the neural network subserving human awareness (21).

The figure above illustrates Mr. Wallis' brain. On the left is a DTI scan to trace fiber tracts. On the right is a PET scan to measure glucose metabolism. The areas highlighted are on the posterior medial surface of the brain, the parietal-occipital region, which includes the cuneus and precuneus.

It's really interesting to compare the DTI scan of Mr. Wallis with that of a control subject, as illustrated below. The first thing to note is the degeneration in Patient 1's corpus callosum (the big red crescent in the middle of the control's brain, labeled cc). This structure is a huge white matter tract that connects the two cerebral hemispheres. But what's most novel is the unique white matter tract in Patient 1's parietal-occipital region. Could this presumed axonal growth be the basis of the remarkable improvement in Mr. Wallis' state of awareness?

Predicting the chances of recovery of consciousness and communication in patients who survive their coma but transit in a vegetative state or minimally conscious state (MCS) remains a major challenge for their medical caregivers. Very few studies have examined the slow neuronal changes underlying functional recovery of consciousness from severe chronic brain damage. A case study in this issue of the JCI reports an extraordinary recovery of functional verbal communication and motor function in a patient who remained in MCS for 19 years (see the related article beginning on page 2005). Diffusion tensor MRI showed increased fractional anisotropy (assumed to reflect myelinated fiber density) in posteromedial cortices, encompassing cuneus and precuneus. These same areas showed increased glucose metabolism as studied by PET scanning, likely reflecting the neuronal regrowth paralleling the patient’s clinical recovery. This case shows that old dogmas need to be oppugned, as recovery with meaningful reduction in disability continued in this case for nearly 2 decades after extremely severe traumatic brain injury.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.